: Chronic low level exposure to environmental toxins impacts on human health by promoting the development of what might otherwise be regarded as normal aging related diseases. Abnormally folded proteins, endogenous proteotoxins, have recently been shown to contribute significantly to degenerative diseases affecting the central and peripheral nervous system, liver, endocrine glands and other organs. Environmental toxins have the potential to modify protein structure directly or indirectly and therefore proteotoxicity is hypothesized to contribute to pathogenesis of many environmentally induced disorders such as Parkinson's disease, Motor Neuron Disease and Cancer. The goal of this program is to define the manner by which environmentally induced changes in protein structure are recognized, to understand how such stress signals are transduced to specific responses and to place these responses in the context of cellular physiology. These studies will impact on environmental health in two ways: First, revealing the details of the cellular adaptation to environmentally-induced proteotoxicity will identify aspects of the response that may be modified to therapeutic ends. Second, by reducing environmentally induced proteotoxicity to its essential molecular components (in much the same way as certain classes of mutagens have been reduced to defined interactions with DNA and chromatin), these studies will provide precise tools for identifying new environmental hazards. Experimentally, the focus will be on stress responses to arsenite, a prototypical toxin thought to exert many of its effects by modifying protein structure. The signaling pathways that link arsenite exposure to the early event of eIF2a phosphorylation will be defined and, utilizing the power of targeted mutagenesis in the mouse, the consequences of interfering with this pathway will be defined functionally. Phosphorylation of eIF2a is an upstream signal that controls stress-induced gene expression. The complement of genes controlled by this pathway will be revealed, using a combination of bioinformatics and functional genomics. The last aim is to use the power of genetic screens to define early events in a signaling pathway that specifically responds to arsenite and activates a novel arsenite-induced gene, Airap/aip- 1. Identification of these early steps will likely provide molecular clues as to the nature of the proximal macromolecular targets of environmental proteotoxicity.